Treatment of bone marrow edema (oedema) with polysulfated polysaccharides

ABSTRACT

A method for the treatment of bone marrow edema in a mammal comprising administering an effective amount of a polysulfated polysaccharide including salts thereof, to a mammal in need of such treatment.

The present application is a continuation of U.S. patent applicationSer. No. 13/983,406, filed Oct. 1, 2013, which was a U.S. Nationalapplication based on Patent Cooperation Treaty Application No.PCT/AU2012/000091, filed on Feb. 2, 2012, which claims the benefit ofAustralian Application No. 2011900325, filed on Feb. 2, 2011, each ofwhich is incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to the medical use of sulphated polysaccharidesfor the treatment of a symptomatic bone marrow edema that may be presentwithin the musculoskeletal system of a mammal.

BACKGROUND OF THE INVENTION

Bone marrow edema (BME) is a common multifactorial disorder which canoccur in isolation and in association with several other medicalconditions such as bone fractures, chronic use of steroid therapies(hypocortisonism), alcohol abuse, activated protein C (APC) resistance,prothrombin mutations or hyperhomocysteinaemia and rheumatoid arthritis.However, the appearance of bone marrow lesions in subjects with no knownpre-existing disorders normally associated for bone marrow lesions hasled to the classification of the condition as bone marrow edema syndrome(BMES). These types of BME are readily identified using magneticresonance imaging (MRI) and are generally, but not invariably,accompanied by pain at rest and on undertaking physical activities[1-5]. Bone marrow edema has also been described as bone bruising, bonemarrow contusions or bone marrow lesions and is frequently associatedwith a previous traumatic injury. For example 80% of patients who hadsustained an acute anterior cruciate ligament (ACL) rupture of the kneejoint or a similar post-traumatic joint injury exhibits the symptoms ofpain emanating from the joint accompanied by regions of decreased signalintensity on T1-weighted images and increased signal intensity onT2-weighted MRI images of the bone marrow spaces within the joint. SuchMRIs images are consistent with localisation of interstitial fluid atsite(s) within the bone marrow and are normally located directlyadjacent to the areas where the highest contact injury was sustained[1-8]. With the ACL tears the subchondral bone marrow beneath thelateral femoral condyl and the posterior-lateral tibial plateau show themost significant MRI signals but other sites such as ligament insertionpoints which are also subjected to high tensional stress are may oftenbe implicated. The size of the BME, as determined by MRI, has beenreported to correlate with the intensity of activity and rest pain inthe patient's knee joint. Moreover, it was noted from MRI follow-upsthat a reduction in the size of the lesions was generally associatedwith a decrease in joint pain [1-8].

Although MRI is clearly the most reliable non-invasive methodology forthe diagnosis of BME there is still ongoing debate as to the mostappropriate MR pulse signals that would optimize the assessment of BMEand achieve semi-quantification of its magnitude. This point issignificant in regard to correlations of BME with indices of pain andjoint function and how these parameters respond to various modalities ofmedical treatments. In a recently published study [9] thesemi-quantitative assessment of subchondral BME lesions and subchondralcysts was compared using intermediate-weighted (IW) fat-suppressed (fs)spin echo and Dual Echo Steady State (DESS) sequences on a three Teslar(3T) MRI instrument. This investigation showed that the IW fs sequenceidentified more subchondral BME lesions and better qualified the extentof their size. While the DESS sequence improved the differentiation ofsubchondral BME lesions from subchondral cysts, the IW fs sequence wasconsidered superior for the determination of lesion size [9]. The futureapplication of intermediate-weighted (IW) fat-suppressed (fs) spin echosignal analysis coupled with higher resolution MRI instrumentation willundoubtedly serve to improve the quantification of BME and demonstratethe ubiquity of these lesions as the underlying cause of pain andfunctional disability in acute musculoskeletal disease and disorders.

In this respect subchondral or osteochondral injuries resulting in BMEhave also been recorded for the hip joint [10,11], foot and ankle joints[12-13] wrist joints [14] and vertebral bodies of the spinal column[15]. Interestingly, even low impact mechanical stress across joints canprovoke a painful BME as was described for a patient who after a rightknee medial collateral ligament sprain was prescribed the use of alateral shoe wedge to correct for the medial compartment compression.After using the orthotic device for some weeks the patient presentedwith worsening pain and an increase in MRI lesion intensity.Discontinuation of the use of the insole reduced the pain and eliminatedthe BME [16].

Subchondral BME is not confined to synovial joints. The pubic symphysisis an amphi-arthrodial joint composed of two pelvic bones connected by awedge shaped fibrocartilagenous disc. Beneath the interface of thefibrocartilagenous attachment to the bone plate resides the trabecularbone containing marrow. The trabecular bone in response to intensemechanical stresses, particularly tensional/rotational distraction, canundergo fatigue stress injuries leading to micro fractures andculminating in bone marrow edema. These types of pelvic injuries havebeen described collectively as groin pain, sports hernia (misnomer),athletic pubalgia, or osteitis pubis. It is seen most frequently inelite athletes, particularly long distance runners, soccer players,tennis players and Australian Rules football (AFL) players [17-19]. Inthe AFL studies it was shown that the incidence of pubic BME, as definedby the MRI signal intensities, was 77%. These bone marrow lesions werealso associated with other MRI abnormalities includingfibrocartilagenous cysts and secondary degenerative changes in the pubicsymphysis. The MRI abnormalities correlated with a players past historyof groin pain and tenderness of the pubic symphysis as was determinedclinically [17]. It is significant that in a recent publication from theAFL it was reported that groin pain (including osteitis pubis) was oneof the three most consistent causes of loss of player time in the AFL[20].

As already indicated an increase in interstitial fluid in subchondralbone marrow is an expression of BME. Such subchondral lesions, ifuntreated, can progress to bone necrosis and trabecular bone fracturesand loss (localized osteoporosis) thereby weakening the underlyingmechanical support for the overlaying articular cartilage. In addition,the subsequent disorganized repair of the damages subchondral bonestructures can lead to thickening and stiffening of the subchondral boneplate rendering it less compliant to mechanical deformation on loadingthereby conferring higher localized stresses on the adjacent articularcartilage thus accelerating its degeneration and progression toosteoarthritis (OA) [21, 22]. It would be expected therefore that thereshould exists a strong association between the topographical locationsof subchondral BME and degenerative changes in the adjacent articularcartilage and the progression of OA. Support for this interpretation wasprovided in a recent study where, subchondral BME (reported as cysts)were detected by T1-weighted fat suppressed MRI in 47.7% of OA patientsat entry. Over a two years follow-up period the severity of the cystsMRI hyper-signal correlated with OA disease progression, as determinedby cartilage volume loss in the medial compartment and the risk ofreceiving a total joint replacement [23]. Since many younger individualswith BME do not present with accompanying radiological or MRI evidenceof OA it would seem that cartilage degeneration, which is considered asa characteristic pathological feature of OA joints, may arise as asecondary event to pre-existing BME. This conclusion is consistent withthe early studies of Radin and colleagues who postulated that failure ofsubchondral trabecular bone (as exists in BME lesions) followed by itsmechanical stiffening and reactivation of centers of secondaryossification (calcified cartilage) due to the disorganized repair was aprimary cause of OA [21,22].

Additional support for the traumatic stress origin of BME or cysts hasbeen provided by a study of racehorses [24]. The proximal metacarpalregion of the performance racehorse is a frequent site of lameness.However, the origin of the pain has hitherto been difficult to diagnoseprecisely. Review of standing MRI images of the proximalmetacarpus/distal carpus of a group of lame horses revealed extensivehyper intensity of the T2 gradient echo signals and a decrease inintensity of the T1 images in the third metacarpal bone that wasconsistent with a pre-existence of BME which from the literature citedherein, provided an explanation for the origin of the lameness [24].

The traditional medical treatments for symptomatic BME are rest andimmobilization of the affected joints/anatomical region. The symptoms ofpain and joint dysfunction may resolve spontaneously over 3-12 months,however, the quality of life of the patient during this period can besubstantially diminished. With post-surgical patients and others whohave BME identified by MRI analgesics or non-steroidal anti-inflammatorydrugs (NSAIDs) are often prescribed. The rationale for the use of thesedrugs for this condition is that they will abrogate the symptoms of BME.However, there is no evidence that these drugs can achieve anybeneficial effect since they have little or no therapeutic effect on theunderlying pathophysiology responsible for BME. In some instancesinjections of corticosteroids have been used to treat BME, particularlyin elite sports persons whose presence on the field of play isconsidered critical to the outcome of the game. On the basis of a wellestablished literature [25-30] which has shown that NSAIDs andcorticosteroids in particular, have negative effects on the metabolismof cartilage and bone, such medications would be contra-indicated asthey could hinder the natural tissue healing process. Moreover,corticosteroids can even exacerbate the problem because of their knownpro coagulant, antifibrinolytic and osteoporotic inducing effects[28-30]. Such pharmacological activities would delay the clearing ofthrombi from marrow spaces and arrest new bone deposition within thebone marrow lesion sites.

Heparin and structurally related polysulfated polysaccharides such aspentosan polysulfate, chitosan polysulfate, the fucans etc have beenused for a number of years as anticoagulants [31-36]. Pentosanpolysulfate (PPS) is a weaker anticoagulant than heparin [31,33,35] buthas been used post-surgically and prophylactically as a thrombolyticagent [36]. However, when given via the oral and intrathecal routes, PPSis currently prescribed for the treatment of interstitial cystitis(inflammation of the bladder) [37-39]. PPS has also been proposed as adisease modifying drug for OA [40] and has demonstrated symptomaticrelief in patients with OA [41, 42].

SUMMARY OF THE INVENTION

We have discovered that pentosan polysulfate (PPS) or a structurallyrelated polysulfated polysaccharides when administration orally orsystemically to a mammal with BME, as identified by the symptoms of painand impaired function together with radiographic or MRI evidence of thelocalised collapse of trabecular bone and the presence of interstitialfluid in the bone marrow spaces of its musculoskeletal system, cantherapeutically resolve the clinical symptoms and diminish the size ofthe BME. It has also been discovered by the inventor that (PPS) or astructurally related polysulfated polysaccharides can attenuate thelocal production of Tumor Necroses Factor Alpha (TNF-α) by cells in theBME which is postulated as the primary mediator of vascular and cellularchanges that gives rise to the pain resulting from this and relatedmedical conditions.

Accordingly, the present invention consists in a method for thetreatment of bone marrow edema in a mammal comprising administering aneffective amount of a polysulfated polysaccharide to a mammal in need ofsuch treatment.

In another aspect, the present invention consists in a compositioncomprising an effective amount of a polysulfated polysaccharide and apharmaceutically acceptable carrier for the treatment of bone marrowedema in a mammal.

In a further aspect, the present invention consists in the use of apolysulfated polysaccharide in the manufacture of a medicament for thetreatment of bone marrow edema.

For purposes of clarity, bone marrow edema (BME) may be defined asfollows: Occult injuries to the bone are often referred to as bonebruises or bone contusions and are readily demonstrated radiographicallyor by magnetic resonance imaging (MRI) as bone marrow cysts or bonemarrow edema. These lesions appear as decreased signal intensity on MRIT1-weighted images and increased signal intensity on T2-weighted images.The MRI signals are thought to arise from increase concentration ofinterstitial fluids in areas of trabecular micro fractures and collapsewithin the bone marrow. These lesions may be the consequence of a directblow to the bone, compressive forces of adjacent bones impacting on eachother, or traction forces that occur during an avulsion injury such asat the site of attachment of a ligament or tendon to a bone. In othersituations excessive rotational/shearing/extensional stresses as mayoccur in certain sporting activities may provoke the occurrence ofedematous lesions within tissues as frequently seen in the pubicsymphysis and diagnosed as “groin pain”.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is not to betaken as an admission that any or all of these matters form part of theprior art base or were common general knowledge in the field relevant tothe present invention as it existed before the priority date of eachclaim of this application.

This invention is directed to treatments of mammals. However, unlessspecifically indicated in the description of the invention is to beunderstood to be applicable to humans and other mammals unlessspecifically indicated otherwise. Amongst other mammals may be mentioneddomestic pets, such as cats and dogs, farm animals such as cattle,sheep, goats, horses, camels, etc as well as those mammals that usuallyexist in the wild but may be susceptible to treatment by virtue of suchmammals being situated in zoos, wildlife parks and the like.

DESCRIPTION OF THE INVENTION

The polysulfated polysaccharide family can be considered to be anynaturally occurring or semi-synthetic/synthetic polysulfatedpolysaccharide or a biologically active fragment thereof that containstwo or more sugar rings to which one or more sulfate ester groups arecovalently attached as exemplified by heparin and pentosan polysulfate.

Preparation of the polysulfate polysaccharide-metal complexes isdescribed in detail in U.S. Pat. No. 5,668,116, the entire disclosure ofwhich is incorporated herein by reference.

Further information relating to polysulfate polysaccharides and PPS canbe found in WO 02/41901, the entire disclosure of which is incorporatedherein by reference.

According to a preferred embodiment, the polysulfated polysaccharide tobe used in this invention can be selected from, but are not limited to,naturally occurring high molecular weight heparin, low molecular weightheparins, the heparan sulfates, pentosan polysulfate, chondroitinpolysulfate, chitosan polysulfate, dermatan polysulfate sulodexide,dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide,sulfated bis-aldonic acid amide, sucrose octasulfate, fucoidan-1,fucoidan-2, sulfated beta-cyclodextrin, sulfated gamma-cyclodextrin andsmall sulfated compounds including, but are not limited to, inositolhexasulfate,

Therefore in one embodiment, the present invention consists in a methodfor the treatment of bone marrow edema in a mammal comprisingadministering an effective amount of a polysulfated polysaccharide,including salts thereof, selected from the group consisting of highmolecular weight heparin, low molecular weight heparins, the heparansulfates, pentosan polysulfate, chondroitin polysulfate, chitosanpolysulfate, dermatan polysulfate sulodexide, dextran sulfate,polysulfated inulin, sulfated lactobionic acid amide, sulfatedbis-aldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2,sulfated beta-cyclodextrin, sulfated gamma-cyclo dextrin and smallsulfated compounds including, but are not limited to, inositolhexasulfate, to a mammal in need of such treatment.

In another embodiment, the present invention consists in a compositioncomprising an effective amount of a polysulfated polysaccharideincluding salts thereof, selected from the group consisting of naturallyoccurring high molecular weight heparin, low molecular weight heparins,the heparan sulfates, pentosan polysulfate, chondroitin polysulfate,chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate,polysulfated inulin, sulfated lactobionic acid amide, sulfatedbis-aldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2,sulfated beta-cyclodextrin, sulfated gamma-cyclodextrin and smallsulfated compounds including, but are not limited to, inositolhexasulfate, and a pharmaceutically acceptable carrier for the treatmentof bone marrow edema in a mammal.

In another embodiment, the present invention consists in the use of apolysulfated polysaccharide including salts thereof, selected from thegroup consisting of naturally occurring high molecular weight heparin,low molecular weight heparins, the heparan sulfates, pentosanpolysulfate, chondroitin polysulfate, chitosan polysulfate, dermatanpolysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfatedlactobionic acid amide, sulfated bis-aldonic acid amide, sucroseoctasulfate, fucoidan-1, fucoidan-2, sulfated beta-cyclodextrin,sulfated gamma-cyclo dextrin and small sulfated compounds including, butare not limited to, inositol hexasulfate, in the manufacture of amedicament for the treatment of bone marrow edema.

The preferred polysulfated polysaccharides include: pentosan polysulfatechondroitin polysulfate, chitosan polysulfate and heparin (high and lowmolecular weight fractions). See also British and US Pharmacopeia's forfull description of heparin, fractionated heparin, and pentosanpolysulfate structure and methods of identification.

Therefore in one embodiment, the present invention consists in a methodfor the treatment of bone marrow edema in a mammal comprisingadministering an effective amount of a polysulfated polysaccharideincluding salts thereof, selected from the group consisting of highmolecular weight heparin, low molecular weight heparins, pentosanpolysulfate, chondroitin polysulfate and chitosan polysulfate to amammal in need of such treatment.

In another embodiment, the present invention consists in a compositioncomprising an effective amount of a polysulfated polysaccharideincluding salts thereof, selected from the group consisting of highmolecular weight heparin, low molecular weight heparins, pentosanpolysulfate, chondroitin polysulfate and chitosan polysulfate and apharmaceutically acceptable carrier for the treatment of bone marrowedema in a mammal.

In another embodiment, the present invention consists in the use of apolysulfated polysaccharide including salts thereof, selected from thegroup consisting of high molecular weight heparin, low molecular weightheparins, pentosan polysulfate, chondroitin polysulfate and chitosanpolysulfate in the manufacture of a medicament for the treatment of bonemarrow edema.

The preferred polysulfated polysaccharides are pentosan polysulfate, thesodium salt of pentosan polysulfate (NaPPS), the magnesium salt ofpentosan polysulfate (MgPPS), and/or the calcium salt of pentosanpolysulfate (CaPPS).

Therefore in one embodiment, the present invention consists in a methodfor the treatment of bone marrow edema in a mammal comprisingadministering an effective amount of a polysulfated polysaccharideselected from the group consisting of pentosan polysulfate, the sodiumsalt of pentosan polysulfate (NaPPS), the magnesium salt of pentosanpolysulfate (MgPPS), and/or the calcium salt of pentosan polysulfate(CaPPS) to a mammal in need of such treatment.

In another embodiment, the present invention consists in a compositioncomprising an effective amount of a polysulfated polysaccharide selectedfrom the group consisting of pentosan polysulfate, the sodium salt ofpentosan polysulfate (NaPPS), the magnesium salt of pentosan polysulfate(MgPPS), and/or the calcium salt of pentosan polysulfate (CaPPS) and apharmaceutically acceptable carrier for the treatment of bone marrowedema in a mammal.

In another embodiment, the present invention consists in the use of apolysulfated polysaccharide including salts thereof, selected from thegroup consisting of pentosan polysulfate, the sodium salt of pentosanpolysulfate (NaPPS), the magnesium salt of pentosan polysulfate (MgPPS),and/or the calcium salt of pentosan polysulfate (CaPPS) in themanufacture of a medicament for the treatment of bone marrow edema.

The most preferred polysulfated polysaccharide is the sodium pentosanpolysulfate manufactured to the specifications lodged with the US FDAand European Community EMEA by Bene-PharmaChem GmbH & Co KG, Geretsried,Germany.

Therefore, in one embodiment, the present invention consists in a methodfor the treatment of bone marrow edema in a mammal comprisingadministering an effective amount of sodium pentosan polysulfate to amammal in need of such treatment.

In another embodiment, the present invention consists in a compositioncomprising an effective amount of sodium pentosan polysulfate and apharmaceutically acceptable carrier for the treatment of bone marrowedema in a mammal.

In another embodiment, the present invention consists in the use ofsodium pentosan polysulfate in the manufacture of a medicament for thetreatment of bone marrow edema.

The methods of manufacture, isolation and purification together withsuitable carriers compositions and formulations are incorporated intothe present application.

The term polysulfated polysaccharides and hypersulfated polysaccharidecan be used interchangeably.

In the present invention, administration of PPS may be by injectionusing the intra-muscular (IM) and sub-cutaneous (SC) routes or it couldbe administered intra-venously (IV), intra-articularly (IA),peri-articularly, topically, via suppositories or orally. The injectionroute is preferred.

Therefore in one embodiment, the present invention consists in a methodfor the treatment of bone marrow edema in a mammal comprisingadministering by a method selected from injection using theintra-muscular (IM) or sub-cutaneous (SC) routes, intra-venously (IV),intra-articularly (IA), peri-articularly, topically, via suppositoriesor orally, an effective amount of a polysulfated polysaccharideincluding salts thereof, selected from the group consisting of highmolecular weight heparin, low molecular weight heparins, the heparansulfates, pentosan polysulfate, chondroitin polysulfate, chitosanpolysulfate, dermatan polysulfate sulodexide, dextran sulfate,polysulfated inulin, sulfated lactobionic acid amide, sulfatedbis-aldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2,sulfated beta-cyclodextrin, sulfated gamma-cyclodextrin and smallsulfated compounds including, but are not limited to, inositolhexasulfate, to a mammal in need of such treatment.

In another embodiment, the present invention consists in a compositioncomprising an effective amount of a polysulfated polysaccharideincluding salts thereof, selected from the group consisting of naturallyoccurring high molecular weight heparin, low molecular weight heparins,the heparan sulfates, pentosan polysulfate, chondroitin polysulfate,chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate,polysulfated inulin, sulfated lactobionic acid amide, sulfatedbis-aldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2,sulfated beta-cyclodextrin, sulfated gamma-cyclodextrin and smallsulfated compounds including, but are not limited to, inositolhexasulfate, and a pharmaceutically acceptable carrier for the treatmentof bone marrow edema in a mammal by administering the composition by amethod selected from injection using the intra-muscular (IM) orsub-cutaneous (SC) routes, intra-venously (IV), intra-articularly (IA),peri-articularly, topically, via suppositories or orally.

In another embodiment, the present invention consists in the use of apolysulfated polysaccharide including salts thereof, selected from thegroup consisting of naturally occurring high molecular weight heparin,low molecular weight heparins, the heparan sulfates, pentosanpolysulfate, chondroitin polysulfate, chitosan polysulfate, dermatanpolysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfatedlactobionic acid amide, sulfated bis-aldonic acid amide, sucroseoctasulfate, fucoidan-1, fucoidan-2, sulfated beta-cyclodextrin,sulfated gamma-cyclo dextrin and small sulfated compounds including, butare not limited to, inositol hexasulfate, in the manufacture of amedicament for the treatment of bone marrow edema by administering thepolysulfated polysaccharide by a method selected from injection by theintra-muscular (IM) or sub-cutaneous (SC) routes, intra-venously (IV),intra-articularly (IA), peri-articularly, topically, via suppositoriesor orally.

For the last 50 years or so Bene-PharmaChem has supplied their PPS in 1ml glass ampoules containing 100 mg PPS/ml. Because of the readyavailability of this sterile injectable product it is preferred to beused in the present invention.

Typically, about 1 to 2 mg/kg PPS, that is 1 to 2 ampoules of theBene-PharmaChem injectable formulation is administered at each dosingfor an average 70 kg individual. For heavier or lighter weightedindividuals the PPS dose of 1-2 mg/kg would be adjusted accordingly.However, for convenience a single dose, for example of 200 mg PPS,dissolved in 2 ml of an appropriate buffer could be prepared as a 2 mlprefilled sterile syringe to avoid the necessity of opening the glassampoules and filing a syringe before administering the injection.

For veterinary applications 10 ml vials containing 1000 mg PPS (orlarger PPS amounts) could be used for multidose use from which areadministered as about 2-3 mg/kg PPS by aspirating the required volumewith a sterile syringe. Such dosing would be applicable, for example, inthe treatment of horses where larger quantities of PPS are requiredbecause of the higher mass of these patients.

For human treatment, one regimen may comprise 5-10×1 ml ampoules or3-6×2 ml prefilled syringes of the Bene-Pharmachem PPS administered oncea day or thrice weekly depending on the severity of the pain experiencedby the patient.

However, in some instances where a patient is experiencing high levelpain, it is desirable to reach a therapeutic loading of the PPS asquickly as possible. This may necessitate, for example, theadministration of about 1.0 mg/kg or more PPS daily until the pain isresolved.

For example, in one instance, the pain suffered by a patient was sodebilitating that the patient received a total of 7 intramuscularinjections (7×1 ml ampoules PPS [7×100 mg]) over a period of 7 day untilthe pain resolved. This equated to just over 1.0 mg/kg PPS daily.

When the PPS is administered by injection, this would normally becarried out in a clinical situation where the PPS would be administeredby a nurse/doctor. In such circumstances, it is to be expected that 2-3visits (injections) per week over several weeks would constitute asufficient treatment regimen. The key to successful treatment is toadminister sufficient PPS to the patient to achieve an optimumtherapeutic dose in the vicinity of the tissue lesion. Since PPSaccumulates in connective tissues, loading can be achieved over time, egdaily doses of 1 mg PPS/kg (100 mg PPS ampoule) for 7-10 days or 2 mgPPS/kg daily (2×100 ml PPS ampoules or 1×2 ml pre-filled syringe) over4-5 days. Using such protocols the patient should eventually receive atotal of about 200-2000 mg PPS, preferably about 1000 mg as course oftreatment.

From a safety point of view the lower dose range (1-2 mg PPS/kg) over alonger period (5-10 days) is preferred. This is because PPS is a knownanticoagulant and the basal APT may be elevated with the higher dose (>3mg PPS/kg) which could potentially encourage bleeding of any openwounds.

For administration by IV infusion, the lower doses of 0.5-1 mg PPS/kgdaily are preferred.

Whilst administration by injection is preferred, oral or topicalformulations of PPS may be used as follow-up (maintenance dose) for theinitial IM or SC PPS treatments. This would also be applicable to oraldosing using, for example, 100 mg capsules of NaPPS on a daily basis,the Calcium PPS derivative being preferred.

The Calcium PPS can be prepared by exchange of the sodium ions of theBene NaPPS or by neutralization of the hydrogen form of PPS with calciumhydroxide.

It will be recognized by persons skilled in the art, that compositionssuitable for administration by a variety of routes may be formulated byreference to standard textbooks in this field, such as Remington'sPractice of Pharmacy. These compositions include by injection, oral(including tablets and capsules containing gastro-intestinal drugabsorption extenders and enhancers), intravenous and the like.

The determination of the suitability of the treatment of the presentinvention or in other words the diagnosis of bone marrow edema may beestablished through the use of MRI together with the symptom of pain.For example, as decreased signal intensity on MRI T1-weighted images andincreased signal intensity on T2-weighted images

In order to better understand the nature of this invention, a number ofexamples will now be described.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is an MRI (T1 weighted scans) of subject PR showing the presenceof bone marrow edema in the subchondral bone of the in left femoralcondyle. Edema is evidenced by the reduced intensity of the signals inthe semi-circular region beneath the articular cartilage. The MRI wastaken 5 days following initial joint injury; and

FIG. 1B is an MRI (T1 weighted scans) of subject PR taken one week aftercompleting a course of 10×100 mg/ml IM injection of pentosanpolysulfate. Note the absence of bone marrow edema in left femoralcondyle. Magnification of MRI image shown is slightly higher than forFIG. 1A.

EXAMPLES EMBODIMENTS

A. A method for the treatment of bone marrow edema in a mammalcomprising administering an effective amount of a polysulfatedpolysaccharide including salts thereof, to a mammal in need of suchtreatment.

B. A composition comprising an effective amount of a polysulfatedpolysaccharide including salts thereof, and a pharmaceuticallyacceptable carrier for the treatment of bone marrow edema in a mammal.

C. Use of a polysulfated polysaccharide including salts thereof, in themanufacture of a medicament for the treatment of bone marrow edema.

D. A method according to Example Embodiment A, a composition accordingto Example Embodiment B or a use according to Example Embodiment Cwherein the polysulfated polysaccharide is selected from the groupconsisting of high molecular weight heparin, low molecular weightheparins, the heparan sulfates, pentosan polysulfate, chondroitinpolysulfate, chitosan polysulfate, dermatan polysulfate sulodexide,dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide,sulfated bis-aldonic acid amide, sucrose octasulfate, fucoidan-1,fucoidan-2, sulfated beta-cyclodextrin, sulfated gamma-cyclodextrin andsmall sulfated compounds including, but are not limited to, inositolhexasulfate.

E. The method, the composition or the use according to ExampleEmbodiment D wherein the polysulfated polysaccharide is selected fromthe group consisting of high molecular weight heparin, low molecularweight heparins, pentosan polysulfate, chondroitin polysulfate andchitosan polysulfate.

F. The method, the composition or the use according to ExampleEmbodiment E wherein the polysulfated polysaccharide is selected fromthe group consisting of pentosan polysulfate, the sodium salt ofpentosan polysulfate (NaPPS), the magnesium salt of pentosan polysulfate(MgPPS), and the calcium salt of pentosan polysulfate (CaPPS).

G. The method, the composition or the use according to ExampleEmbodiment F wherein the polysulfated polysaccharide is sodium pentosanpolysulfate.

H. The method, the composition or the use according to ExampleEmbodiments A to G wherein treatment is by administering an injection bythe intra-muscular (IM) or sub-cutaneous (SC) routes, intra-venously(IV), intra-articularly (IA), peri-articularly, topically, viasuppositories or orally.

I. The method, the composition or the use according to ExampleEmbodiment H wherein the treatment is by administering an injection.

J. The method, the composition or the use according to ExampleEmbodiments A to I wherein the effective amount is about 1 to 2 mg/kg ofthe mammal per dose.

K. The method, the composition or the use according to ExampleEmbodiment J wherein administration to a human is by dosing in atreatment regimen once daily or thrice weekly.

L. The method, the composition or the use according to ExampleEmbodiment K wherein the total dose of polysulfated polysaccharideadministered in the treatment regimen is about 200-2000 mg.

MODES FOR CARRYING OUT THE INVENTION Examples Example 1

A male subject (PR) aged 53 years in good general health while joggingon the footpath stumbled and fell laterally striking the pavement withhis right knee. Next day the knee was swollen and extremely painful andwhen examined by a medical practitioner was diagnosed as avulsion of thecollateral ligament attachment to tibial bone. This diagnosis wasconfirmed by MRI that also showed the presence of a large subchondralBME in the femoral subchondral bone (FIG. 1A). Five days aftersustaining the injury surgical repair was undertaken to re-attach thefree ligament bone insertion to the tibia. However the knee painpersisted thereafter and was not relieved by use of analgesics orNSAIDs. Five weeks after the surgery a course of PPS, 100 mg/mlinjections administered intramuscularly twice weekly for 5 weeks wasinitiated (total of 10 injections). After receiving the 6th injection,the pain and joint swelling had disappeared and one week aftercompletion of the PPS course of injections the joint was again reviewedby T1 weighted MRI. As is evident from FIG. 1B the BME present at theonset of PPS treatment had completely resolved following theadministration of PPS.

Example 2

A retired female figure ice-skater (JP), 26 years of age and in goodhealth, fell heavily on her ankle while moving house. The ankle showedextensive bruising and she rested the joint for one week and to someextent the pain was relieved. However, the pain was still intense onweight-bearing and JP consulted her orthopaedic foot specialist whoreferred her to a physiotherapist for treatment. After 6 weeks ofphysiotherapy the swelling and bruising had declined but painoriginating from the ankle joint was still present, particularly onweight-bearing. A second visit to the orthopaedic specialist resulted ina MRI scan that revealed BME in the impacted bones of the joint.Although JP was advised to continue physiotherapy by her orthopaedicspecialist, the pain still persisted but would have been resolved by acourse of 6 subcutaneous injections of PPS (100 mg) over 10 days.

Example 3

A healthy 70 year-old male (PG) with genu varum of approximately 5degrees slipped on a step at an airport terminal while rushing to catchan international flight such that his left foot made an unexpected highimpact with the ground. After arriving at his destination late thatevening, PG retired for the night but was woken in the early hours ofthe morning with intense throbbing pain originating from the medialcompartment of his left knee joint. Oral analgesics every 3 hours failedto significantly diminish the knee pain and next day PG commenced acourse of intra-muscular injections of PPS (100 mg) administered daily.Following the 5th injection the knee pain had substantially subsided andwas completely resolved after the 7th injection. The debilitating jointpain experienced by this individual following the sub-chondral bonecontusion (BME) incurred by the sudden high mechanical impart did notre-occur in subsequent months following the PPS course of therapy whichwas consistent with the resolution of the BME.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the scope of theinvention as broadly described. The present embodiments are, therefore,to be considered in all respects as illustrative and not restrictive.

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The invention claimed is:
 1. A method for the treatment of bone marrowedema in a mammal not suffering from osteoarthritis, comprisingadministering intra-articularly or peri-articularly from about 1 mg/kgto about 2 mg/kg per dose of a polysulfated polysaccharide selected fromthe group consisting of pentosan polysulfate, the sodium salt ofpentosan polysulfate (NaPPS), the magnesium salt of pentosan polysulfate(MgPPS), and the calcium salt of pentosan polysulfate (CaPPS) to amammal in need of such treatment.
 2. The method according to claim 1wherein the polysulfated polysaccharide is sodium pentosan polysulfate.3. The method according to claim 1, wherein treatment isintra-articularly (IA).
 4. The method according to claim 1, wherein thetreatment is peri-articularly.
 5. The method according to claim 1,wherein administration is to a human and is by dosing in a treatmentregimen once daily, twice weekly, or thrice weekly.
 6. The methodaccording to claim 1, wherein the total dose of polysulfatedpolysaccharide administered in the treatment regimen is from about 200mg to about 2000 mg.